Coelho 2012.

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group
Participants	Outpatients Setting: 8 centres in Argentina, Brazil, France, Germany, Portugal (2 centres), Spain, and Sweden Number: 128 randomised participants. ITT population (all randomised participants who received at least 1 dose of study medication and who had at least 1 post‐baseline assessment for both co‐primary endpoints or who discontinued due to LT): 125 participants (64 in the tafamidis group, 61 in the placebo group) Mean (SD) age (ITT population): 39.8 ± 12.7 years in the tafamidis group, 38.4 ± 12.9 years in the placebo group. Age was > 65 years in 5/64 (7.8%) of participants in the tafamidis group and in 3/61 (4.9%) in the placebo group Gender (ITT population): males were 32/64 (50.0%) in the tafamidis group and 26/61 (42.6%) in the placebo group Race (ITT population): White were 56/64 (87.5%) in the tafamidis group and 54/61 (88.5%) in the placebo group Median (IQR) disease duration (ITT population): 28.0 months (IQR 13.8 to 41.7) in the tafamidis group, 21.0 months (IQR 13.5 to 72.2) in the placebo group Key inclusion criteria: age 18 to 75 years inclusive; TTR‐FAP with documented Val30Met mutation in the TTR gene and biopsy‐confirmed amyloid deposits; peripheral or autonomic neuropathy with a Karnofsky ≥ 50 Key exclusion criteria: presence of primary amyloidosis, other causes of sensorimotor neuropathy, absence of a recordable sensory threshold for vibration perception in both feet, liver function test abnormalities, prior LT, renal insufficiency (creatinine clearance < 30 mL/min), New York Heart Association classification ≥ 3, any comorbidity anticipated to limit survival to < 18 months, chronic use of non‐protocol‐approved nonsteroidal anti‐inflammatory drugs
Interventions	Tafamidis meglumine 20 mg once daily (N = 65) Placebo (N = 63) Oral self‐administration Duration of treatment period: 18 months
Outcomes	Co‐primary endpoints (time point: 18 months): NIS‐LL responders to treatment ("responders" were participants with decrease from baseline or increase from baseline of 0 to < 2 in the NIS‐LL score); change from baseline in the Norfolk QOL‐DN total score. Secondary endpoints: NIS‐LL responders to treatment at months 6 and 12 ("responders" were participants with decrease from baseline or increase from baseline of 0 to < 2 in the NIS‐LL score); continuous analysis of the change from baseline to months 6, 12, and 18 in the NIS‐LL score; change from baseline to 6 and 12 months in the Norfolk QOL‐DN total score; change from baseline to months 6, 12, and 18 in the 5 domains of the Norfolk QOL‐DN total score; change from baseline to month 18 in summated 7‐composite and 3‐composite scores; change from baseline to months 6, 12, and 18 in mBMI; TTR stabilisation at 18 months, as measured by a validated immunoturbidimetric assay; incidence of participants experiencing treatment‐emergent serious adverse events; incidence of participants experiencing treatment‐emergent Grade 3 adverse events; incidence of participants experiencing treatment‐emergent Grade 3 clinical laboratory findings; incidence of participants with treatment‐emergent echocardiography findings considered by the Investigator to be clinically significant; incidence of participants with treatment‐emergent electrocardiogram findings considered by the Investigator to be clinically significant; incidence of participants discontinuing from the study because of clinical or laboratory adverse events.
Funding	Support from: FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010; NIH grant DK 46335; FDA Orphan Drug grant FD‐R‐00(03414‐01).
Conflicts of interest among main investigators	T Coelho's institution received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010. T Coelho received support from Pfizer Inc. M Waddington‐Cruz, O Suhr, and IM Conceicao received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010, and from Pfizer Inc. V Planté‐Bordeneuve, P Lozeron, HHJ Schmidt, and P Trigo received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010. JM Campistol received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010, and from Wyeth (Pfizer Inc.). JW Kelly was founder, shareholder and option holder, and paid consultant of FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010. J Chan, R Labaudiniere, J Packman, A Wilson, and DR Grogan were employees of FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010, during the conduct of the study.
Notes	ClinicalTrials.gov Identifier: NCT00409175 Clinicaltrialsregister.eu Identifier: 2006‐002792‐41 Information obtained from both published report papers and online clinical trial registries Maximum duration of study: 20 months (screening period: 1 month, treatment period: 18 months, final telephone contact: 1 month after the last dose of study medication) Dates: 2007 to 2009
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomized by a central computerized telerandomization system, in a 1:1 ratio". Comment: probably done
Allocation concealment (selection bias)	Low risk	Quote: "Patients were randomized by a central computerized telerandomization system, in a 1:1 ratio, to self‐administer [...] tafamidis [...] or matching placebo. [...]". Comment: probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "double‐blind trial". "Patients were randomized by a central computerized telerandomization system, in a 1:1 ratio, to self‐administer [...] tafamidis [...] or matching placebo. [...] The active drug was provided in soft‐gelatin capsules [...]. The packaging, appearance, and constitution of the placebo capsules were identical to those of the active‐drug capsules except for the absence of tafamidis". Quote (from the final public disclosure synopsis provided by Pfizer Inc.): "Blinded safety summaries were provided [...] 24 months after enrollment commenced. [...] An interim efficacy and safety analysis was conducted [...]. The interim analysis was unblinded, but the blind remained unbroken for subjects and Investigators, and the Sponsor was not aware of the results of the interim analysis". Quote (from ClinicalTrials.gov): "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)". Comment: probably done
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "double‐blind trial"; "Patients returned to the clinical sites during the double‐blind treatment period". Quote (from the final public disclosure synopsis provided by Pfizer Inc.): "Blinded safety summaries were provided [...] 24 months after enrollment commenced. [...] An interim efficacy and safety analysis was conducted [...]. The interim analysis was unblinded, but the blind remained unbroken for subjects and Investigators, and the Sponsor was not aware of the results of the interim analysis". Quote (from ClinicalTrials.gov): "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)". Comment: probably done, but the statistical analysis was conducted by an employee of the sponsor.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "The primary efficacy analyses were performed on the intent‐to‐treat (ITT) population (all randomized patients who received at least 1 dose of study medication and who had 1 postbaseline assessment for both coprimary endpoints or who discontinued due to liver transplantation). For patients with postbaseline assessments, the last‐observation‐carried‐forward method was used to impute missing data at month 18"; "Analyses of the coprimary endpoints were performed in an efficacy‐evaluable (EE) population consisting of ITT patients who completed the study per protocol. This EE population was prespecified as it was anticipated that the majority of patients enrolled would be on the liver transplant list and that many would undergo liver transplantation during the study if a donor organ became available"; "Analyses of the secondary endpoints were conducted in the ITT population using a repeated measures analysis of variance model [...] Only observed values were used". Comment: there was a high dropout rate in this RCT. As the original protocol of this RCT was not accessible, we could not verify whether populations on which analyses of the outcomes have been performed were prespecified. Some continuous outcome data of interest for this review were only descriptively presented and no measures of variability were published so that they cannot be entered in a meta‐analysis. For dichotomous outcomes most data were obtained from unpublished data.
Selective reporting (reporting bias)	Low risk	Comment: results for all predetermined outcomes were obtained by either published reports, online clinical trial registries, or both.
Other bias	Unclear risk	Comment: this study was funded by FoldFox Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010. Most Investigators received funding from the Sponsor or were employees of the Sponsor during the conduct of this trial.